ARTICLE IN BRIEF
The article features research on synaptic signaling and how new insights about it are fueling understanding of the pathophysiology of a vast range of brain disorders — from epilepsy, to Rett syndrome, to Alzheimer's disease.
Gina G. Turrigiano, PhD, has dedicated her career to working out the complexities of synaptic scaling, the process by which neurons maintain a functional level of excitability — neither too much, which could lead to seizures, nor too little, which could lead to catatonia.
In a special lecture at this year's Society of Neuroscience annual meeting, she described her research and how it is being applied to other findings on therapeutic targets for a vast array of brain disorders. [For related research by other investigators, see “Supporting Evidence on Synaptic Signaling” on neurotodayonline.com.]
Synaptic scaling depends on continuous feedback between neurons, which control their transmission strength by increasing or decreasing the number of receptors on the post-synaptic membrane, Dr. Turrigiano explained. For example, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors — the most common type of receptor in the brain — diffuse freely around the synapse and attach to the post-synaptic membrane. An increase in AMPA receptors post-synaptically facilitates neural transmission, while a decrease inhibits it.
In her lab at Brandeis University, where she is a professor of biology, Dr. Turrigiano and her colleagues have probed this process by perturbing the function of rat cortical networks in vitro. They slow synaptic signaling with tetrodotoxin, a neurotoxin found in pufferfish, toads, and other species, which binds to sodium channels and blocks presynaptic spikes that increase synaptic strength. They boost signaling with bicuculline, a molecule that blocks the inhibitory activity of postsynaptic gamma-aminobutyric acid (GABA) receptors, allowing synapses to fire excessively. Then the researchers try to figure out how neurons return to a state of homeostasis.
“These experiments suggested to us that neurons have a target firing rate, and if forces push them beyond that rate, neurons reduce their excitability to bring the firing rate back,” she explained. “If we blocked activity, all excitatory currents got larger in amplitude, and if we raised activity, all excitatory currents got smaller. It was as though neurons had a synaptic thermostat they could turn up or down to compensate for these changes.”
Evolution has made this homeostatic process robust and reliable, but the sheer complexity of synaptic scaling leaves opportunities for malfunction. And even when neurons struggle valiantly to maintain normal transmission strength in the face of Alzheimer's disease, schizophrenia, or some other disruption, they can become overwhelmed and fall out of balance.
“This is still speculative, but we think it's likely that circuits of neurons can't function properly without these homeostatic mechanisms,” Dr. Turrigiano told Neurology Today. “And if they go awry, potentially that could contribute to a wide range of neurological dysfunction.”
One obvious consequence of homeostatic failure would be synaptic over-excitation resulting in epilepsy. “We know perturbing the balance of excitation and inhibition in cortical or hippocampal circuits leads to epileptic-like activity,” she said.
Elly Nedivi, PhD, a professor of neurobiology in the department of brain and cognitive sciences at Massachusetts Institute of Technology, has been collaborating with Dr. Turrigiano to characterize the effects of synaptic scaling on mutations associated with risk for bipolar disorder. They have a paper under review that describes the mechanism of a candidate gene Dr. Nedivi has dubbed CPG2 for “candidate plasticity gene 2,” which encodes a protein involved in regulating glutamate receptor internalization in certain synapses in the cortex, hippocampus, striatum, and cerebellum.
“I think people have different polymorphisms that potentially work better or worse at the synapse, and in some genetic constellations there is an ability to compensate for the low functioning variants, which coincides with how neuropsychiatric disorders work,” said Dr. Nedivi. “It's not that if you have the gene, you're well and if you don't, you're sick. It has this strange penetrance whereby even identical twins can differ.”
SYNAPTIC SCALING, OTHER BRAIN DISORDERS
Synaptic scaling also appears to play a significant role in Rett syndrome, a neurodevelopmental disorder of the gray matter caused by a loss-of-function mutation in the gene coding for methyl-CpG binding protein 2 (MeCP2). Dr. Turrigiano and her collaborator, Sacha B. Nelson, MD, PhD, professor of biology at Brandeis University, recently published a paper in the Journal of Neuroscience showing that the loss of MeCP2, which results in a decrease in glutamatergic synapses in the cortex and hippocampus of mice, produces a decline in excitatory signaling and prevents synaptic scaling. These results “raise the possibility that some of the neurological defects of Rett arise from a disruption of homeostatic plasticity,” the authors concluded.
Kara Pratt, PhD, a former graduate student in Dr. Turrigiano's lab and now an assistant professor in the department of zoology and physiology at the University of Wyoming, has linked synaptic scaling to mutations in presenilin 1, one of the major risk factors for Alzheimer's disease. In a 2011 paper in Nature Neuroscience, she and her colleagues described how mouse hippocampal cells lacking presenilin 1 failed to scale up their synaptic strengths in response to chronic tetrodotoxin treatment to inhibit their excitation; this suggests that the mutation promotes Alzheimer's disease at least in part by disrupting synaptic scaling.
“Maybe aging circuits start to lose their pep, and when they need to scale up the ones without proper presenilin 1, they have deficits, which would explain why symptoms aren't experienced until later in life,” Dr. Pratt suggested.
Dr. Turrigiano's postdoc advisor, Eve Marder, PhD, has done her own work on homeostasis, but marvels at where her former student has taken synaptic plasticity.
“Gina took the work she did as a post-doc on homeostatic regulation of intrinsic excitability and made a quantum leap in our understanding,” said Dr. Marder, Victor and Gwendolyn Beinfield professor of neuroscience and chair of the biology department at Brandeis University, and a member of the US National Academy of Sciences. “I think she is uncovering some of the fundamental principles that allow us to understand how synaptic strength regulation in the brain occurs, with potential applications most immediately to our understanding of how activity controls normal development of brain circuits.”
FOR MORE ABOUT SYNAPTIC SIGNALING AND NEURODEGENERATIVE DISEASE:
- Neurology Today archive on synaptic signaling: http://bit.ly/YKSSbJ
- Neurology journal archive on synaptic signaling: http://bit.ly/TzP9r2
- NINDS resources, programs and reports on channels, synapses, and neural circuits: http://1.usa.gov/Rz3B6X
FOR FURTHER READING:
• Turrigiano GG. The self-tuning neuron: Synaptic scaling of excitatory synapses. Cell
• Jiang M, Zhu J, Shu Y, et al. Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex. PLoS Biology
• Turrigiano GG, Nelson SB. Homeostatic plasticity in the developing nervous system. Nature Rev Neurosci
• Fröhlich F, Bazhenov M, Sejnowski TJ. Pathological effect of homeostatic synaptic scaling on network dynamics in diseases of the cortex. J Neurosci
• Blackman MP, Djukic B, Turrigiano GG, et al. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci
• Zhong X, Li H, Chang Q. MeCP2 Phosphorylation is required for modulating synaptic scaling through mGluR5. J Neurosci
• Qiu Z, Sylwestrak EL, Ghosh A, et al. The Rett syndrome protein MeCP2 regulates synaptic scaling. J Neurosci
• Small DH. Network dysfunction in Alzheimer's disease: Does synaptic scaling drive disease progression? Trends Mol Med
• Pratt KG, Zimmerman EC, Cook DG, and Sullivan JM. Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nature Neuroscience
• Fujino T, Wu Z, Lin WC, Phillips MA, Nedivi E. cpg15 and cpg15–2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival. J Comp Neurol